Widespread plasticity in CTCF occupancy linked to DNA methylation

Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
Genome Research (Impact Factor: 14.63). 09/2012; 22(9):1680-8. DOI: 10.1101/gr.136101.111
Source: PubMed


CTCF is a ubiquitously expressed regulator of fundamental genomic processes including transcription, intra- and interchromosomal interactions, and chromatin structure. Because of its critical role in genome function, CTCF binding patterns have long been assumed to be largely invariant across different cellular environments. Here we analyze genome-wide occupancy patterns of CTCF by ChIP-seq in 19 diverse human cell types, including normal primary cells and immortal lines. We observed highly reproducible yet surprisingly plastic genomic binding landscapes, indicative of strong cell-selective regulation of CTCF occupancy. Comparison with massively parallel bisulfite sequencing data indicates that 41% of variable CTCF binding is linked to differential DNA methylation, concentrated at two critical positions within the CTCF recognition sequence. Unexpectedly, CTCF binding patterns were markedly different in normal versus immortal cells, with the latter showing widespread disruption of CTCF binding associated with increased methylation. Strikingly, this disruption is accompanied by up-regulation of CTCF expression, with the result that both normal and immortal cells maintain the same average number of CTCF occupancy sites genome-wide. These results reveal a tight linkage between DNA methylation and the global occupancy patterns of a major sequence-specific regulatory factor.

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Available from: Rajinder Kaul
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    • "Super-enhancers are highly cell type-specific (Whyte et al. 2013), but the majority of CTCF binding sites are constitutive (Wang et al. 2012). Previous studies found significant enrichment of motifs for cell-type-specific transcription factors , but not CTCF, at super-enhancers in ES cells and in B cells (Hnisz et al. 2013; Whyte et al. 2013). "
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    • "Next, we examined if CTCF binds to the differentially methylated CGI-2. When searching the publicly available CTCF ChIP-seq data from the human ENCODE project [33] [34] [35], we found four CTCF binding peaks around human miR-1188 (Fig. S1A). Sequence alignments showed all CTCF binding sites are conserved between human and mouse. "
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    • "Strikingly, they could demonstrate that CTCF binding is dramatically different between primary and immortal cell lines. The latter harbors widespread disruption of CTCF sites associated with increased methylation [77]. Taken together, CTCF/cohesin co-bound sites appear to be responsible, at least in part, for the configuration of topological domain structure. "
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